Olanzapine is an antagonist of D-1 and D-2 dopamine receptors and also exhibits antimuscarinic and anticholinergic properties and antagonist activity at 5HT-2 receptor sites. Olanzapine also acts as an antagonist of noradrenergic alpha-receptors. These properties indicate that olanzapine may possess relaxant, anxiolytic, or anti-emetic properties and may be suitable for use as an a neuroleptic. Olanzapine is therefore useful in treating psychotic conditions including schizophrenia, schizophreni-form diseases, and acute mania. Olanzapine can additionally be used in the treatment of mild anxiety states when administered at lower doses.
Clinical evaluations of psychiatric patients suffering from schizophrenia have shown that olanzapine exhibits high levels of activity at surprisingly low dosage levels, making it a highly desirable therapeutic candidate for the treatment of psychotic patients. Unfortunately, olanzapine typically exhibits a color which is undesirable for commercial pharmaceutical use, especially as the color changes over time on exposure to air.
The current methods of synthesizing olanzapine require harsh reaction conditions, such as high temperatures and/or strong bases, such as alkyl lithium bases, with catalysts which may contribute to the undesirable color changes. To achieve the high reaction temperatures necessary in the current methods of synthesizing olanzapine, high boiling solvents that are difficult to remove once the product is obtained are used.
U.S. Pat. No. 5,229,382 discloses olanzapine synthesis by condensation of thienobenzodiazepine (4-amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine) and N-methylpiperazine in a mixture of toluene and dimethylsulfoxide, which are high boiling organic solvents. The yield of the process is relatively low, and the solvent recovery is very difficult.
The invention encompasses methods of synthesizing olanzapine that do not require high boiling solvents or high temperatures.